Agonist anti-trkc antibodies and methods using same

a technology of agonist and antitrkc antibody, which is applied in the direction of peptides, drug compositions, and infusion cells, can solve the problems of neurotrophin therapy, neurotrophins, neurotrophins, and neurotrophins, and achieve the effects of reducing the number of nt-3

Active Publication Date: 2009-08-13
NXP BV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0039]In some embodiments, the polypeptides or antibodies of the invention do not include the exclusions described herein. With respect to the formulae herein, as is evident to the one skilled in the art, each amino acid substituent may be independently selected. The invention also provides formulae in one or more amino acid substituents are eliminated.

Problems solved by technology

As a result, it is difficult to devise therapies that target a specific population of neurons.
Another limitation of neurotrophin therapy is that neurotrophins, including NT-3, are known to elicit hyperalgesia (Chaudhry et al., Muscle and Nerve 23:189-192, 2000).
In addition, some neurotrophins such as NT-3 have poor pharmacokinetic and bioavailability properties in rodents, which raise serious questions about their human clinical applications (Haase et al., J. Neurol. Sci. 160:S97-S105, 1998, dosages used in Helgren et al., J. Neurosci. 17(I):372-82, 1997).
In addition, effector functions of mouse antibodies have proven to be less efficient in the human context.

Method used

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  • Agonist anti-trkc antibodies and methods using same
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Examples

Experimental program
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Effect test

example 1

Humanization and Affinity Maturation of Mouse Monoclonal Antibody 2256

[0228]A. General Methods

[0229]The following general methods were used in this example.

[0230]Expression Vector Used in Clone Characterization

[0231]Expression of the antibodies was under control of an IPTG inducible lacZ promotor similar to that described in Barbas (2001) Phage display: a laboratory manual, Cold Spring Harbor, N.Y., Cold Spring Harbor Laboratory Press pg 2.10. Vector pComb3X), however, modifications included addition and expression of the following additional domains: the human Kappa light chain constant domain and the CH1 constant domain of IgG2a human immunoglobulin. Ig gamma-2 chain C region, protein accession number P01859; Immunoglobulin kappa light chain (homo sapiens), protein accession number CAA09181.

[0232]Small Scale Fab Preparation

[0233]Small scale expression of Fab in 96 wells plates was carried out as follows. Starting from E. coli transformed with a Fab library, colonies were picked to...

example 2

Effect of Antibody A5 on Pyridoxine-Induced Neuropathy

[0255]Treatment protocol. The experiments were carried out on adult male Sprague-Dawley rats weighing 150 to 200 g at the start of the experiment, and in compliance with approved institutional animal care and use protocols. Six to eight animals were used for each treatment group. Neuropathy was induced by the injection of pyridoxine (PDX, Sigma, St. Louis, Mo.) at 100 mg / ml in distilled water immediately before injection, and administration was performed at 400 mg / kg intraperitoneally twice a day for 8 days. A5-treated animals received A5 (5 mg / kg) by intraperitoneal injection 3 days before the start of PDX treatment, and again at 1 week after the initial dose of A5. Vector-treated animals received a single subcutaneous inoculation of 25 ul of vector QL2HNT3 (1×109 pfu / ml) in the plantar surface of both hind feet 3 days prior to the start of intoxication. Vector QL2HNT3 is a replication-incompetent, genomic herpes simplex virus-b...

example 3

Effect of Antibody A5 on Ciplatin-Induced Neuropathy

[0260]Treatment protocol. The experiments were carried out on female Wistar rats weighing 180-200 g (Harlan, Correzzana, Italy) at the start of the experiment. Animals were divided by computer-generated random selection into the different groups and eight animals were used for each treatment group. Neuropathy was induced by intraperitoneally (ip) injection of cisplatin (CDDP) (Bristol Meyer Squibbs, at 0.5 mg / ml in sterile saline) at 2 mg / kg twice weekly for four weeks. Group 1 animals (controls) were untreated. Group 2 animals were injected with CDDP at 2 mg / kg ip twice weekly for four weeks. Group 3 animals were injected with CDDP at 2 mg / kg ip twice weekly for four weeks and subcutaneously (sc) injected with antibody 2256 at 2 mg / kg once every 7 days. Group 4 animals were injected with CDDP at 2 mg / kg ip twice weekly for four weeks and subcutaneously injected with antibody 2256 at 10 mg / kg once every 7 days. Group 5 animals were...

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Abstract

The invention concerns agonist anti-trkC antibodies, polypeptides, and polynucleotides encoding the same. The invention further concerns use of such antibodies, polypeptides and/or polynucleotides in the treatment and/or prevention of neuropathies, such as sensory neuropathies, including taxol-induced sensory neuropathy, cisplatin-induced sensory neuropathy, and pyridoxine-induced sensory neuropathy.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the priority benefit of provisional application U.S. Ser. No. 60 / 532,592, filed Dec. 23, 2003, which is incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The invention concerns agonist anti-trkC antibodies and polypeptides. The invention her concerns use of such antibodies and polypeptides in the treatment and / or prevention of diseases, such as sensory neuropathy.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0003]Not applicable.BACKGROUND OF THE INVENTION[0004]Neurotrophins are a family of small, homodimeric proteins, which play a crucial role in the development and maintenance of the nervous system. Members of the neurotrophin family include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 / 5 (NT-4 / 5), neurotrophin-6 (NT-6), and neurotrophin-7 (NT-7). Neurotrophins, similar to other polypeptide growth factors, affect the...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C07K16/18C12N15/11C12N15/00C12N5/06C12P21/08C07K16/28
CPCA61K2039/505C07K16/2863C07K2317/92C07K2317/24C07K2317/56C07K2316/95C07K2317/75A61P25/00C07K16/28G01N33/53
Inventor PONS, JAUME
Owner NXP BV
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